Genetic Basis of Haematological Cancers

Written by a team of international experts, this book provides an authoritative overview and practical guide to the molecular biology and genetic basis of haematologic cancers including leukemia. Focusing on the importance of cytogenetics and related assays, both as diagnostic tools and as a basis for translational research, this is an invaluable guide for basic and clinical researchers with an interest in medical genetics and haemato-oncology. The Genetic Basis of Haematological Cancers reviews the etiology and significance of genetic and epigenetic defects that occur in malignancies of the haematopoietic system. Some of these chromosomal and molecular aberrations are well established and already embedded in clinical management, while many others have only recently come to light as a result of advances in genomic technology and functional investigation. The book includes seven chapters written by clinical and academic leaders in the field, organised according to haematological malignancy sub-type. Each chapter includes a background on disease pathology and the genetic abnormalities most commonly associated with the condition. Authors present in-depth discussions outlining the biological significance of these lesions in pathogenesis and progression, and their use in diagnosis and monitoring response to therapy. The current or potential role of specific abnormalities as novel therapeutic targets is also discussed. There is also a full colour section containing original FISH, microarrays and immunostaining images.

Auteur
Dr Sabrina Tosi graduated in Biological Sciences at the University of Milan (Italy) in 1989 and then attained her post-graduate degree in Human Cytogenetics at the University of Pavia (Italy) in 1992. Her interest in leukaemia dates back to 1989, when she started to work as a research scientist in the Department of Paediatric Haematology, Ospedale San Gerardo, Monza (Italy). In 1991-1992 Dr Tosi spent a year in the Oncogenetic Laboratory, Children's Hospital, University of Giessen (Germany) as a visiting research scientist. After another two years in Monza, Dr Tosi moved to the University of Oxford at the Weatherall Institute of Molecular Medicine, where she attained her DPhil in 1999 and spent altogether 12 years in leukaemia research. In 2005 she was appointed as Lecturer in Biosciences at Brunel University London, where she continues to work on the contribution of chromosomal abnormalities to leukaemia, with particular interest towards paediatric leukaemia.

Dr Alistair Reid graduated in Genetics from the University of Newcastle upon Tyne in 1995, and trained as a diagnostic genetic scientist in the UK heath service. He obtained his PhD in Cambridge in 2003 based on the characterization of novel genetic prognosticators in myeloid leukemia. Since then he has held positions at several clinical academic haematology centres including Royal Free, London and University Children's Hospital, Zurich, and has also spent time as a consultant in the genetic diagnostics industry. In 2006 he was appointed Consultant Clinical Scientist in Molecular Pathology at Imperial College Healthcare Trust in London. He has an active laboratory-based translational research program focused on the genetics of myeloid leukemia and holds an honorary senior clinical lectureship for the development of novel methods of personalized genetic management in malignancy. Dr Reid has contributed to over 60 papers on malignancy genetics and was awarded fellowship of the Royal College of Pathologists in 2011.

Contenu

List of contributors xi

Preface xiii

**1 The myelodysplastic syndromes 1
Cristina Mecucci, Valeria Di Battista and Valeria Nofrini

Introduction 1

Predisposing conditions 2

Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) 2

Severe congenital neutropenia (SCN) 5

Poikiloderma with neutropenia 6

Familial MDS/AML 6

ShwachmanDiamond syndrome (SDS) 7

Dyskeratosis congenita (DKC) and telomere syndromes 8

Fanconi anaemia (FA) 11

Down syndrome 12

Cytogenetics 12

Loss of Y chromosome (Y) and del(11q) 13

Del(20q) 15

idic(X)(q13) 15

Del(17)(p13)/i(17q) 15

Del(12p) 16

Trisomy 8 16

Rare trisomies: +6, +13, +14, +15, +16, +19, +21 16

Monosomy 7 and del(7q) 17

Rare monosomies 19

Unbalanced translocations involving 1q 19

t(17;18)(p10;q10) 20

Rare or sporadic balanced translocations 20

Complex karyotypes 22

Chromosome 5q deletions 23

Somatic mutations 31

Oncogenes and tumour suppressor genes 31

Mutations of genes involved in epigenetic modulation 39

Mutations of genes involved in the spliceosome machinery 45

Rare gene mutations in myelodysplastic syndromes 48

Epigenetics 49

DNA methylation 50

Histone modifications 52

RNA 53

Conclusion 54

References 54

**2 Molecular genetics of the myeloproliferative neoplasms 80
Philip A. Beer

Introduction 80

Overview of the different types of mutation found in MPN patients 80

Acquired mutations in cytokine signalling pathways 82

Acquired mutations in pathways controlling transcriptional regulation 84

Acquired mutations associated with transformation to advanced-phase disease 87

Inherited predisposition to clonal MPNs 87

Inherited non-clonal disorders that phenocopy distinct MPNs 87

Polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) 88

Acquired mutations in cytokine signalling pathways (Table 2.3) 89

Acquired mutations in pathways controlling transcriptional regulation (Table 2.4) 95

Acquired mutations associated with progression to advanced and blastic-phase disease 101

Inherited predisposition to clonal MPNs 103

Inherited non-clonal disorders that phenocopy distinct MPNs 104

Principles and clinical utility of laboratory testing 107

Chronic eosinophilic leukaemia 109

Acquired mutations in cytokine signalling pathways 109

Acquired mutations in pathways controlling transcriptional regulation 113

Acquired mutations associated with progression to advanced and blastic-phase disease 113

Inherited predisposition to clonal MPNs 113

Inherited non-clonal disorders that phenocopy distinct MPNs 114

Principles and clinical utility of laboratory testing 114

Neoplastic mast cell disease 115

Acquired mutations in cytokine signalling pathways 116

Acquired mutations in pathways controlling transcriptional regulation 118

Acquired mutations associated with progression to advanced and blastic-phase disease 118

Inherited predisposition to clonal MPNs 119

Inherited non-clonal disorders that phenocopy distinct MPNs 119

Principles and clinical utility of laboratory testing 120

References 121

**3 Acute myeloid leukaemia 133
Matthew L. Smith and Thomas McKerrell

Introduction 133

AML classification 134

Cytogenetic aberrations 135

Fusion genes arising from structural rearrangements 135

Monosomies 148

Complex and monosomal karyotypes 148

Trisomies 148

Double minute chromosomes 151

Normal karyotype is it really normal? 151 Altered...